This invention relates to an implant composition for the controlled release of macromolecular drugs. More specifically the present invention relates to a composition having a core comprising a biologically active macromolecular drug and a polymer and a homogenous polymer membrane coating containing a uniformly distributed water-soluble pore-forming agent.
The administration of therapeutic dosages of low molecular weight drugs has traditionally been accomplished by simple ingestion. Ingestion of macromolecular drugs, however, is not always feasible. Where low concentrations are loaded in a tablet, the rapid passage of materials through the body can render the tablets impracticable due to the number of tablets necessary to achieve the therapeutic dosage over time. When high concentrations are loaded, potentially harmful quantities can be released during the short residence period. In other cases the acidic environment of the stomach is destructive to the drug resulting in denaturization and/or acid hydrolysis.
Although some of these problems may be alleviated by implant methods of administration, the achievement of a substantially linear release of a macromolecular drug has yet to be accomplished. This can be attributed in part to difficulties in developing an effective rate limiting coating for the drug. Some research, however, has been directed toward perfecting controlled release systems.
U.S. Pat. No. 3,773,919 discloses a biodegradable controlled release composition having a core of a macromolecular antibiotic polypeptide, microencapsulated with polylactides and their glycolide copolymers. European Pat. No. 52 510 A2 similarly discloses microencapsulation of water soluble antibiotic polypeptides using synthetic biodegradable polymers such as polylactones and related polymers.
Biodegradable microencapsulation for the sustained release of enzymes, hormones, vaccines and other biologicals is discussed in Chang, Journal of Bioengineering, Vol. 1, pp. 25-32, (1976). Several examples of encapsulated water soluble proteins are disclosed therein, especially asparagine and insulin compositions.
In these references, diffusion of the core drug is dependent on the natural porosity of the polymer coating, subsequent pore formation in the coating due to polymer solubility and degradability, and in part on the solubility of the encapsulated drug.
Kallstrand et al., (1983) Journal of Pharmaceutical Science, Vol. 72, No. 7, pp. 772-775, describes a drug delivery system for controlling the diffusion rate which consists of a soluble tablet core surrounded by a porous membrane coating. The coating is formed by using a suspension of a water soluble pore-forming agent, e.g., sucrose, in an organic solution of a water insoluble polymer, e.g., an acetone solution of polyvinyl chloride. Sucrose's insolubility in the acetone solvent causes it to remain as a suspension of particulates in the polymer solution. Unfortunately, these particulates have a tendency to form larger aggregates when the coating is formed. When these aggregates are subsequently leached in an aqueous environment, a non-homogeneous pore structure results.